The Conundrum Posed by Cellular Heterogeneity in Analysis of Human Neuroblastoma

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Examining the methylation patterns of gene promoters has become a powerful tool in the effort to identify and distinguish different tumor subtypes ( 1 , 2 ). Typically associated with tumor suppressor genes, epigenetic silencing of gene expression has been seen in several different cancers. Aberrant hypermethylation has been recorded for genes that function in various aspects of cancer biology, including cell cycle regulation, tumor suppression, apoptosis, and metastasis. The article by Alaminos et al. ( 3 ) in this issue is a clear extension of this previous research.

DNA methylation silences gene expression through the addition of methyl groups to cytosine residues of CpG-rich islands present in the promoter region of genes. Whereas housekeeping genes possess CpG regions that are typically unmethylated and therefore transcriptionally active in all cell types, tissue-specific genes are unmethylated in cells actively expressing the genes and are normally methylated in all other differentiated tissues. Patterns of silencing are specified during development; methylation is essential for normal imprinting, X-chromosome inactivation, and differential gene expression during embryonic growth. Changes in DNA methylation patterns have recently been associated with specific cancers, and CpG island hypermethylation profiles for primary tumors have become accepted as a common means to distinguish human cancer subtypes ( 1 , 2 ).